Glioblastomas (GBM) are the most malignant and common intrinsic brain tumor. Despite aggressive treatment the disease is uniformly fatal and patients survive on average less than a year. Our inability to improve disease outcome is due in large part to gaps in our understanding of what mechanisms activate GBM invasion. We first identified the role of TWIST1 in GBM invasion and its high correlation with human GBM malignancy. Its critical function in carcinoma invasion and metastasis by activation of epithelial mesenchymal transition (EMT) suggested that it may function through similar mechanisms to promote GBM invasion. Here we present novel data demonstrating the potential role of the secreted matrix protein POSTN, Akt activation and TWIST1 binding protein interactions in TWIST1 pro-invasive signaling in GBM. We hypothesize that a TWIST1 regulatory mechanism signaling through POSTN and specific Akt isoforms that is in turn regulated by TWIST1 binding partners promotes GBM invasion and malignancy. To address this hypothesis and show the therapeutic potential of targeting this TWIST1 signaling network we will i) determine how inhibition of TWIST1 in human GBM stem cells and in a cre/lox conditional TWIST model influences tumor invasion and malignancy in vivo, ii) define the impact of inhibiting POSTN and specific Akt isoforms to abrogate TWIST1 pro-invasive signaling in vivo, and iii) identify TWIST1 binding partners that regulate TWIST1 invasion in concert with regulation of POSTN and Akt. By demonstrating the importance of this network for GBM invasion we will further validate the relevance of EMT mechanisms in non-epithelial derived cancers. As such, these studies are expected to revolutionize concepts of GBM invasion and accelerate generation of sorely needed therapies that target the most lethal biological feature of these dreaded cancers. PUBLIC HEALTH RELEVANCE: The lack of significant improvement in treatment outcomes for patients with glioblastoma (GBM) for over 30 years is due largely to our failure to address the problem of GBM cell invasion into the brain. TWIST1 is a putative oncogene which promotes carcinoma invasion and metastasis through activation of epithelial mesenchymal transition (EMT). We have now confirmed TWIST1 as a critical mediator of GBM invasion and malignancy and here will establish for the first time the therapeutic relevance of a TWIST1 signaling network through POSTN and Akt, in turn regulated by TWIST1 binding partners. By demonstrating the impact of this novel pro-invasive network in GBM invasion we will validate the importance of EMT related mechanisms for GBM, also expected to have great relevance for a much larger group of invasive carcinomas. This paradigm shift is expected to revolutionize our understanding of invasion in GBM, accelerate discovery of therapeutic targets, and translate into significant improvements in GBM patient outcomes.